Increased PD-1 Expression on Circulating T Cells Correlates with Inferior Outcome after Autologous Stem Cell Transplantation

High-dose chemotherapy followed by autologous stem cell transplantation is a well-established treatment option for multiple myeloma and malignant lymphoma patients. It is able to induce long-term progression-free survival in both patient groups and even cure in aggressive lymphoma patients. However, relapse is common and has been associated with the pace and quality of immunologic reconstitution after transplantation as well as with immune cell exhaustion and immunometabolic defects. We aim to analyze the dynamic of the prototypical exhaustion marker PD-1 on immune cells during reconstitution upon high-dose chemotherapy followed by autologous stem cell transplantation and its impact on progression-free survival. A comprehensive analysis of exhaustion and metabolic markers on immune cells from myeloma and lymphoma patients were analyzed during autologous stem cell transplantation using flow cytometry and NanoString technologies. The expression of PD-1 increases during early reconstitution upon autologous stem cell transplantation on T- and NK-cells as well as monocytes. However, while its expression normalized in NK-cells and monocytes over time, PD-1 expression on T-cells demonstrated a variable course. Noteworthy, lymphoma patients with a continuously increasing PD-1 expression on T-cells upon autologous stem cell transplantation have an inferior median progression-free survival of only 146 days, while median progression-free survival was not reached in those lymphoma patients without such PD-1 expression pattern. T-cells from patients with increased PD-1 expression after autologous stem cell transplantation exhibited an immunometabolic (over-)activation and exhausted phenotype compared to T-cells from patients with a low PD-1 expression upon transplantation including higher levels of the glycolytic pacemaker enzyme hexokinase 2 and the inhibitory receptor CTLA-4. In addition, proliferating Ki-67+ T-cells were more abundant in patients with high PD-1 expression on T-cells than in those with low expression after autologous stem cell transplantation (11,9% vs. 4,2%). PD-1 expression on T-cells might serve as an adverse biomarker for lymphoma patients undergoing autologous stem cell transplantation, however further validation by larger prospective studies is required.